Dispenser comprising hydrophilic osmopolymer

ABSTRACT

A dispensing system is disclosed comprising a wall surrounding a lumen. The lumen comprises (1) a thermo responsive composition comprising a beneficial agent, (2) means for occupying space in the lumen for pushing the thermo responsive composition from the dispensing system, and (3) means for enhancing the amount of the beneficial agent dispensed from the system positioned between the thermo responsive composition and the means for occupying space.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.07/173,479 filed Mar. 24, 1988, now U.S. Pat. No. 4,844,984; issued July4, 1989, which application Ser. No. 07/173,479 is a cont. of applicationSer. No. 06/895,613 filed Aug. 11, 1986, now U.S. Pat. No. 4,772,474issued Sept. 20, 1988, which application Ser. No. 06/895,613 is a div.of application Ser. No. 06/764,143 filed Aug. 9, 1985, U.S. Pat. No.4,624,945 issued Nov. 25, 1986, which application Ser. No. 06/764,143 isa CIP of application Ser. No. 06/590,778 filed Mar. 19, 1984, U.S. Pat.No. 4,595,583 issued June 17, 1986. These applications are assigned toALZA Corporation of Palo Alto, CA, and are incorporated herein byreference and benefit is claimed of their filing dates.

FIELD OF THE INVENTION

This invention pertains to both an novel and useful dispensing system.More particularly, the invention pertains to a dispenser comprising awall that surrounds an inner space housing comprising (1) athermo-responsive beneficial agent formulation, (2) an expandabledriving member (3) means positioned between the thermo-responsivebeneficial agent formulation and the expandable means for increasing theamount of beneficial agent formulation dispensed from the system, and(4) optionally, a density member. The components comprising thedispensing system perform together in harmony for delivering thebeneficial agent formulation at a controlled rate to a fluid, thermalenvironment of use over a prolonged period of time. The inventionpertains also to laminated structures used for manufacturing thedispensing system, to compositions of matter, and to a method foradministering a beneficial agent using the dispenser.

BACKGROUND OF THE INVENTION

There has long been a pressing need in the medical, pharmaceutical andveterinary arts for a dispensing system that is capable of administeringa beneficial agent at a controlled rate over a prolonged period of time.The need exists for increasing the maximum time of therapeuticeffectiveness of beneficial agents, especially for beneficial agentswhose maximum time of therapeutic effectiveness, when administered inconventional dosage forms such as a tablet, is only for a few hours. Apatient using such a conventional form must take repeated dosages atfrequent intervals. Moreover, during intervals between doses thetherapeutic level in the blood decreases due to metabolic activities andthe level can become so low that it is practically ineffective. Also, asa result of frequent doses, the level of medicine available for therapywill fluctuate between doses. The need for a dispenser exists also fordelivering beneficial agents that are difficult to deliver, usuallyattributable to some physical property. For example, beneficial agentsthat are insoluble in aqueous fluids are difficult to deliver becausethey do not form solutions and, accordingly, they cannot be dispensed insolution from a dispensing device. Then, too, many beneficial agentsexhibit lipid solubilities and these agents are difficult to deliver byconventional dosage forms.

Additionally, a need exists for a dispensing system for dispensing abeneficial agent to a ruminant animal. Ruminant animals, includingcattle, sheep, giraffe, deer, goat, bison and camels, and moreparticularly cattle and sheep, comprise an important group of animalsthat require periodic administration of beneficial agents and nutrients.The beneficial agents and nutrients are administered for better healthand for the treatment and alleviation of various conditions. Ruminantshave a complex three or four compartment stomach. The rumen, the largestof the stomach compartments, serves as an important location forreceiving and passing beneficial agents and nutrients into othercompartments, including the abomasum and the intestine.

Presently ruminants are treated by repeated administrations of agentsand nutrients at frequent time intervals. This form of treatment isinconvenient and expensive, and it does not lend itself to good reliabletherapy or nutrition. Additionally, agents and nutrients are orallyadministered in the form of a bolus to ruminants, and this form ofadministration, like other repeated modes of administration, also doesnot lend itself to acceptable therapy or nutrition. Moreover, ruminantsregurgitate what they swallow, they chew their cuds, and they spit outconventional boluses quickly after administration thereof.

There is therefore, in view of the above presentations, a pressing needfor a dispensing system for use with ruminants that will, after a singleadministration, efficiently administer agents and nutrients over aprolonged period of time. There also is a pressing need for a dispensingsystem for a prolonged release of an agent or a nutrient at a controlledrate in the rumen, by a dispensing system that is swallowed easily bythe ruminant and will remain in the rumen for a long period of timewithout being regurgitated or otherwise eliminated from the rumen.

OBJECTS OF THE INVENTION

It is a principle object of this invention to provide both a novel anduseful dispensing system for dispensing a beneficial agent, includingnutrient, which dispensing system fulfills the pressing need known tothe prior art.

It is another object of this invention to provide a dispensing systemthat can deliver a beneficial agent at a controlled rate over aprolonged period of time, thereby overcoming the shortcomings associatedwith the prior art dosage forms.

It is another object of the invention to provide a dispensing systemmanufactured as a dispenser that is self-contained, self-starting andself-powered in a fluid environment of use for dispensing a beneficialagent to the environment of use, including a warm-blooded animal.

It is another object of the invention to provide a dispensing systemcomprising wall means that surrounds and forms a lumen comprising a heatsensitive means containing a beneficial agent, a driving means fordelivering the beneficial agent from the dispensing system, and meansfor increasing the amount of beneficial agent delivered from thedispensing system.

It is another object of the invention to provide a dispensing systemcomprising (1) a wall comprising in at least a part of a compositionpermeable to the passage of fluid, (2) an internal lumen housing (3) athermo-sensitive composition containing a beneficial agent, (4) anexpandable member, and (5) a member for increasing the amount of agentdelivered, for enhancing the delivery profile, and for protecting theagent, and which dispensing system delivers the beneficial agent by thecombined physical-chemical operations of the composition melting orundergoing dissolution to become fluid, semisolid or the like, theexpandable member swelling and occupying space in the area previouslyoccupied by the composition, with the member increasing the amount ofbeneficial agent delivered, thereby dispensing the beneficial agentthrough means in the wall for delivering the beneficial agent over time.

It is another object of this invention to provide a dispensing systemthat delivers a beneficial agent contained in a thermo-responsive,lipophilic pharmaceutical acceptable carrier that softens in thepresence of thermal energY absorbed from the environment of use andthereby forms a dispensable composition that is innocuous and can bedispensed from the dispensing system over time.

It is another object of this invention to provide a dispensing systemcontaining an eutectic composition comprising at least two componentsand at lease one beneficial agent, which eutectic composition has amelting point approximately the same as the temperature of thewarm-blooded animal recipient plus or minus a few degrees thereof, andis dispensed from the dispensing system at said temperature.

It is another object of this invention to provide a dispensing systemcomprising an inner positioned capsule housing a thermo-responsivethermo-responsive hydrophobic composition comprising from insoluble tosoluble agents such as drugs, and which thermo-responsive composition,in response to energy input present in the biological environment ofuse, changes its form and becomes dispensable for operative deliveryfrom the dispensing system.

It is another object of this invention to provide a dispensing systemcomprising a capsule containing a temperature-sensitive composition, anexpandable member, and a densifier in parallel arrangement, an outerwall comprising totally or in part a semipermeable compositionsurrounding the capsule, and a dispensing passageway useful fordispensing a beneficial agent to an animal.

It is another object of this invention to provide a dispensing systemthat can remain in the rumen of a ruminant for a prolonged period oftime.

It is another object of this invention to provide a dispenser for use inanimals, including ruminants, that delivers a beneficial agent includingmedicines and nutrients, and which dispenser is easy to manufacture at alesser cost thereby increasing the usefulness of the dispenser foradministering the agent over a prolonged Period of time.

It is another object of the invention to provide a dispenser comprisinga dense member for keeping the dispenser in the rumen over time, whereinthe dispenser delivers a composition that is a complete pharmaceuticaldosage regimen for a prolonged period of time, the use of whichdispenser requires intervention only for the initiation of the regimen.

It is another object of this invention to provide a composition ofmatter comprising a beneficial agent and a heat sensitive compositionuseful for manufacturing a dispensing device.

It is another object of this invention to provide a dispensing systemfor dispensing a beneficial agent to an animal, including a human, whichdispensing system comprises an inner capsule body containing athermoplastic composition and an expandable composition, and a densemember when the dispensing system is used with a ruminant, and whichcomposition includes a beneficial agent that is insoluble or soluble inan aqueous environment and can be housed in the dispensing system in anonaqueous carrier that can be delivered to an animal.

Other objects, features and advantages of the invention will be moreapparent to those skilled in the dispensing art from the followingdetailed description of the specification, taken in conjunction with thedrawings and the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the drawing figures areas follows:

FIG. 1 is a view of a dispensing system designed for orallyadministering a beneficial agent to a warm-blooded animal;

FIG. 2 is an opened view of the dispensing system of FIG. 1, forillustrating the structure of the dispensing system comprising anoutside wall, an inside wall, a thermo-responsive composition, anexpandable member, a dense member, and a member for assuring the releaseof agent from the dispensing system;

FIG. 3, is an opened view of FIG. 1, opened through the vertical lengthof the dispensing system, for illustrating another embodiment comprisinga first and second lamina for enhancing the effectiveness of thedispensing system;

FIG. 4 is an opened view of the dispensing system depicting a wallcomprising in at least a part a semipermeable composition surrounding alumen with the dispensing system comprising all the elements set forthabove designed to act in concert for the controlled delivery of abeneficial agent over time;

FIG. 5 is an opened view of the dispensing system depicting a wallcomprising in at least a part a semipermeable composition surrounding alumen comprising the elements as set forth above with the systemhousing, additionally, a first and second lamina for enhancing thedispensing ability of the system.

FIG. 6 is an opened view of a dispensing system provided by theinvention depicting a different internal structural configuration of theinternal elements comprising the dispensing system and the exterior wallof varying thickness which wall increases in thickness from its lead endto its terminal end;

FIG. 7 is an opened view of a dispensing system provided with adifferent internal arrangement of the internal members comprising thedispensing system;

FIG. 8 is an opened view of the dispensing system of FIG. 7 illustratingthe system with a single wall and a pair of internal members inoperation delivering a beneficial agent over time;

FIG. 9 is an opened view of another embodiment of the dispensing systemcomprising a wall surrounding an internal lumen housing a heat sensitiveformulation, an expandable member and a lamina position between the heatsensitive formulation and the expandable member, and which dispensingsystem optionally omits a density member;

FIG. 10 is an opened view of a dispensing system similar to thedispensing system of FIG. 9, with the dispensing system of FIG. 10embodying more than one passageway for releasing a beneficial agentformulation from the system;

FIG. 11 is an opened view of a dispensing system similar to thedispensing system of FIG. 9 with the dispensing system of FIG. 11housing a first and second lamina;

FIG. 12 is an opened view of a dispensing system similar to FIG. 10 withthe dispensing system of FIG. 12 housing a first and second lamina;

FIG. 13 is an opened view of a dispensing system comprising an exteriormicroporous wall that provides structural support for the system withthe pores of wall a means for releasing a beneficial agent from thesystem;

FIG. 14 illustrates a cross-section of a laminate provided by theinvention comprising a heat-responsive lamina, an intermediate laminafor keeping the integrity of the laminate, and an expandable lamina;

FIG. 15 illustrates a cross-section of a laminate comprising aheat-sensitive lamina, an intermediate lamina for maintaining theintegrity of the laminate, an expandable lamina, and a dense lamina forkeeping the device housing the laminate in an environment of use;

FIG. 16 illustrates a cross-section of a laminate comprising aheat-sensitive lamina and a lamina comprising a member selected from thegroup consisting of an ester of a fatty acid and an alcohol, a fattyacid and an alcohol, a saturated hydrocarbon;

FIG. 17 illustrates a lamina comprising a hydrogel in laminararrangement with a lamina comprising an ester of a fatty acid and analcohol, a fatty acid and an alcohol, or a saturated hydrocarbon;

FIG. 18 illustrates the amount of a beneficial agent released over timeby a system provided by the invention; and,

FIG. 19 depicts the cumulative amount of a beneficial agent released bya dispensing system over a prolonged period of time.

In the drawings and in the specifications, like parts in related figuresare identified by like parts. The terms appearing earlier in thespecification and in the description of the drawing figures, as well asembodiments thereof, are further detailed elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWING FIGURES

Turning now to the drawing figures in detail, which are examples of anew and useful beneficial dispensing system, and which examples are notto be construed as limiting, one example of a dispenser is depicted inFIG. 1, identified by the numeral 10. In FIG. 1, dispenser 10 comprisesa body 11 formed of wall means 12 that surrounds and defines an internallumen, not seen in FIG. 1. Dispensing system 10 comprises agent exitmeans 13, indicated by a partial hole in FIG. 1, for dispensing abeneficial agent formulation from dispensing system 10.

FIG. 2 is an opened view of beneficial dispensing system 10 of FIG. 1.Beneficial system 10 of FIG. 2 comprises body 11, wall means 12 anddispensing exit means 13. Wall 12 surrounds an internal capsule wall 14and internal compartment or lumen 15. Wall 12 comprises, in a presentlypreferred embodiment, a semipermeable wall forming composition that issubstantially permeable to the passage of an external fluid, and it issubstantially impermeable to the passage of a beneficial agent and otheringredients contained in dispensing system 10. In another embodimentwall 12 can be formed of a semipermeable composition that partlysurrounds the capsule and the rest of wall 12 can comprise a differentwall forming composition. Wall 12 is non-toxic, it is inert, and itmaintains its physical and chemical integrity, that is, it doesn't erodeduring the dispensing period. System 10, in one presently preferredembodiment, comprises internal wall 14 made in its final manufacture asa single unit capsule body member. In FIG. 2, capsule wall 14 surroundslumen 15. Lumen 15 contains a thermo-responsive heat sensitivecomposition 16, identified by wavy lines, containing a beneficial agent17, represented by dots. Lumen 15 further contains an expandable drivingmeans 18 that is separated from thermo-responsive heat composition 16 bylamina 19. Lamina 19 is positioned between the active formulation 16 andthe expandable driving member 18 for substantially reducing diffusion,migration, entrapment or the like of active agent 17 into expandablemember 18. Lamina 19 also protects active agent formulation 16 frompossible interaction with expandable member 18 thereby improving thestability of agent formulation 16. Additionally, in one presentlypreferred embodiment, lamina 19 is made from a soft or flexible polymercomposition for aiding in pushing the maximum amount of formulation 16containing agent 17, from system 10 as formulation 16 contacts densitymember 20. Thermo-responsive composition 16 and expandable member 18have a shape that corresponds to the internal shape of capsule wall 14and lumen 15. Lumen 15 also contains a dense member 30 or densifier thatis in contact with thermo-responsive composition 16, which dense member20 is positioned in lumen 16 distant from expandable member 18. A means13, illustrated in this embodiment as a passageway 13, extends throughwall 12, inner capsule 14, for connecting the exterior of dispenser 10with the interior of dispenser 10, mainly lumen 15. Dense member 20 hasa bore 21 therethrough for dispensing composition 16 from lumen 15 toexit passageway means 13 for release from dispenser 10. Dense member 12is an important component of delivery system 10 optionally present andused for keeping dispenser 10, when in use, in the rumen of an animalover a prolonged period of time.

FIG. 3 depicts another manufacture provided by the invention. FIG. 3 isan opened view of the dispensing system 10 of FIG. 1, and it comprisesbody 11, an exterior wall 12 of uniform thickness, internal wall 14,internal compartment 15, and exit means 13. System 10 further comprisesa thermo-responsive heat composition 16 containing beneficial agent 17.Thermo-responsive heat composition 16 is, in this manufacture,immediately to exit means 13. Compartment 15 also contains an expandabledriving member 18 separated by first lamina 19 and second lamina 22 fromthermo-responsive composition 16. Driving member 18 is in laminararrangement with, and positioned adjacent to dense member 20. Densemember 20, in FIG. 3, is positioned distant from exit means 13. In FIG.3, dispenser 10 additionally comprises lamina 22. Lamina 22 ispreferably formed of an impervious and rigid material for lessening theincidence of undesirable contamination in compartment 15. Lamina 22 alsois a means for increasing the delivering efficiency of dispenser 10, byinsuring the total force generated by expandable member 18 is appliedagainst heat-responsive formulation 16, containing agent 17, forsqueezing formulation 16 through exit means 13. Lamina 22 functions likea piston and it is so constructed as to movably provide and maintain atight piston-head arrangement between the active agent phase and theexpandable phase in compartment 15. Lamina 22 is frictionally disposed,but it is free to move within dispenser 10 by sliding while at the sametime maintaining the operability of dispenser 10.

FIG. 4 depicts another embodiment provided by the invention. FIG. 4 isan opened view of dispensing system 10 comprising body 11, exterior wall12, that surrounds interior wall 14. Interior wall 14 partiallysurrounds internal compartment 15 and it is provided with an opened endor mouth 23, at the end of device 10. Mouth 23 is a means for providingeasy access to internal lumen 15 for placing therein thermo-responsivecomposition 16 containing beneficial agent 17, density member 20,optional lamina 22 and expandable driving member 18. Lamina 22 transmitsthe full driving force of expanding member 18 against density member 20for urging thermo-responsive composition 16 containing beneficial agent17 through exit means 13 from dispenser 10.

FIG. 5 depicts another embodiment provided by the invention. FIG. 5 isan opened view of dispensing system 10 comprising body 11, exterior wall12 that surrounds interior wall 14. Interior wall 14 partially surroundsinternal compartment 15 except for mouth 23. Dispensing device 10provides a different internal arrangement exemplified by dense member 20immediately adjacent to exit means 13, heat-responsive composition 16containing beneficial active agent 17 in contacting arrangement withdensity member 20, first lamina 19 in laminar arrangement withheat-sensitive composition 16 and expandable member 18 in laminararrangement with the free face of lamina 19. Additionally, exterior wall12 increases in thickness from the dispensing end to the terminal end ofthe device.

FIG. 6 depicts another embodiment provided by the invention. FIG. 6 isan opened view of dispensing system 10 comprising a wall 12 surroundingan internal compartment 15 housing dense member 20, heat-responsivecomposition 16 containing beneficial agent 17, first lamina 19 inlaminar arrangement with second lamina 22 and expandable member 18.

FIG. 7 depicts another embodiment provided by the invention, seen inopened view. Dispensing system 10 in this embodiment comprises, ininternal compartment 15, density member 20, heat responsive composition16 comprising beneficial agent 17, first lamina 19 and expandable member18.

FIG. 8 depicts another embodiment provided by the invention, seen inopened section. Dispensing system 10 in this embodiment comprises wall12 surrounding internal compartment 15 housing next to exit means 13heat-sensitive composition 16 containing beneficial agent 17 incontacting position with first lamina 19 and second lamina 22,expandable member 18 and density member 20 at the trailing end ofdispenser 10.

FIG. 9 depicts another embodiment provided by the invention. In FIG. 9,dispensing device 10 is illustrated in opened section and it comprisesbody 11, wall 12 that surrounds and forms an internal compartment 15.Wall 12 comprises, in a presently preferred embodiment, a semipermeablewall forming composition that is permeable to the passage of an externalfluid and it is substantially impermeable to the passage of a beneficialagent and other ingredients present in compartment 15. Internalcompartment 15 contains heat-sensitive, thermo-responsive composition16, homogeneously or heterogeneously containing beneficial agent 17.Compartment 15 further contains expandable driving member 18, that isseparated from heat-sensitive composition by lamina 19 positioned therebetween. Lamina 19 comprises a polymeric composition that lessensintermixing of heat-sensitive composition 16 and expandable member 18and it is preferably flexible and adopts the internal shape ofcompartment 15. Dispensing device 10 of FIG. 9 is manufactured without adensity member and it is sized and shaped for preferable use in anon-ruminant, such as the body passageway of a warm-blooded animal.

FIG. 10 depicts another embodiment provided by the invention. In theembodiment depicted in FIG. 10, wall 12 comprises in at least a part asemipermeable composition, with the remainder of wall 12 comprising awall forming composition that is an exit means 13 for releasingbeneficial agent 17 from dispensing system 10. In FIG. 10, exit means 13comprises a microporous element comprising at least one pore that is apassageway for releasing beneficial agent 17 from dispensing system 10.

FIG. 11 depicts another embodiment provided by the invention. In FIG. 11dispensing device 10 is similar to device 10 of FIG. 9, with the addedfeature that in FIG. 11 device 10 additionally comprises interposedsecond lamina 22.

FIG. 12 depicts another embodiment provided by the invention. In FIG.12, dispensing device 10 is similar to device 10 of FIG. 10, with theadded structural embodiment in FIG. 12 of interposed second lamina 22.

FIG. 13 depicts device 10 for dispensing beneficial agent 17 whereindevice 10 comprises an exterior microporous wall forming composition 24.Wall 24 contains a pore forming agent that is removed by eroding,leaching or the like, in the environment of use to form at least onepore 25. In another manufacture, microporous wall 24 is preformed and itconsists of a plurality of micropores. In either embodiment, the pores25 are a means for releasing beneficial agent 17, received frompassageway 13, from device 10.

Dispensing device 10 of FIGS. 1 through 13, when in operation, deliversbeneficial agent formulation 17 to an animal fluid environment of use bya combination of thermodynamic and kinetic integrally performedactivities. That is, in operation, heat-sensitive, thermo-responsivecomposition 16 in response to the temperature of an animal recipientabsorbs thermal energy, melts, or softens, or undergoes dissolution orforms a semipaste-like composition for delivering beneficial agent 17through exit means 13. As composition 16 absorbs thermal energy andundergoes change, concomitantly external fluid enters dispenser 10through a fluid permeable component of wall 12 and is absorbed orimbibed by expandable hydrophilic layer 18. External fluid is imbibed byhydrophilic layer 18 to continuously expand and swell causing it toincrease in volume thereby urging it against first lamina 19 and againstfirst lamina 19 and second lamina 22. As expanding layer 18 occupiesspace in compartment 15 it urges the lamina to move against composition16 containing agent 17 and, hence, through means 13 to the exterior ofdispensing system 10. Further in operation, in the dispensing systemscomprising an inner capsule wall when formed of an erodible,dissolvable, or the like, material, the inner thin-walled water solublecapsule member dissolves at a body temperature of 37° C. or more,leaving dispensing device 10 with outer wall 12. The dissolved wall,usually formed of gelatin, or of a gelatin blend, mixed with composition16, and it can also lubricate the inside of surface of wall 12.

While FIGS. 1 through 13 are illustrative of various dispensing systems10 that can be made according to the invention, it is to be understoodthese devices are not to be construed as limiting the invention, asdispenser 10 can take a wide variety of shapes, sizes and forms fordelivering agent 17 to the environment of use. For example, deliverydevice 10 can be designed for oral use for releasing a locally or asystemically acting agent in the gastrointestinal tract over time. Anoral dispensing system can have various shapes and sizes such as roundwith a diameter of 1/8 inch to 15/16 inch, or it can be shaped like acapsule having a range of sizes from triple zero to zero and from 1 to8. Also, dispensing device 10 can be adapted, shaped, sized andstructured as a buccal, cervical, intrauterine, rectal, vaginal, nasal,dermal, subcutaneous and artificial gland device. The dispensing devicecan be used for administering a beneficial agent to animals, includingwarm-blooded mammals, humans, avians, reptiles and pisces. Thedispensing device can be used in hospitals, clinics, nursing homes,farms, zoos, veterinary clinics, sickrooms, and other environments ofuse. The dispensing device also can be used in non-medical applications,such as agricultural, etc.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of this invention, it has now been foundthat wall 12 can be manufactured of a wall forming composition that doesnot adversely affect agent 17, an animal or other host, and it ispermeable in total or in at least a part to the passage of an externalaqueous-type fluid, such as water and biological fluid, while remainingessentially impermeable to the passage of agents, including drugs, andthe like. Typical materials for forming a semipermeable wall 12 includesemipermeable polymers known to the art as osmosis and reverse osmosismembranes. These materials comprise semipermeable homopolymers,semipermeable copolymers, and the like. In one embodiment typicalmaterials include cellulose esters, cellulose monoesters, cellulosediesters, cellulose triesters, cellulose ethers, and celluloseester-ethers, mixtures thereof, and the like. These cellulosic polymershave a degree of substitution, D.S., on their anhydroglucose unit fromgreater than 0 up to 3, inclusive. By degree of substitution is meantthe average number of hydroxyl groups originally present on theanhydroglucose unit that are replaced by a substituting group, orconverted into another groups. The anhydroglucose unit can be partiallyor completely substituted with groups such as acyl, alkanoyl, aroyl,alkyl, alkenyl, alkoxy, halogen, carboalkyl, alkylcarbamate,alkylcarbonate, alkylsulfonate, aklylsulfamate, and like semipermeablepolymer forming groups.

The semipermeable materials typically include a member selected from thegroup consisting of cellulose acylate; cellulose diacylate; cellulosetriacylate; cellulose acetate; cellulose diacetate; cellulosetriacetate; mono-, di- and tri-cellulose alkanylates; mono-, di- andtrialkenylates; mono-, di- and tri-alkenylates; mono-, di- andtri-aroylates and the like. Exemplary polymers including celluloseacetate having a D.S. of 1.8 to 2.3 and an acetyl content of 32 to39.9%; cellulose diacetate having a D.S. of 1 to 2 and an acetyl contentof 21 to 35%; cellulose triacetate having a D.S. of 2 to 3 and an acetylcontent of 34 to 44.8% and the like. More specific cellulosic polymersinclude cellulose propionate having a D.S. of 1.8 and a propionylcontent of 30.5%; cellulose acetate propionate having an acetyl contentof 1.5 to 7% and an acetyl content of 39 to 45%; cellulose acetatepropionate having an acetyl content of 2.5 to 3% an average propionylcontent of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; celluloseacetate butyrate having a D.S. of 1.8, an acetyl content of 13 to 15%,and a butyryl content of 34 to 39%; cellulose acetate butyrate having anacetyl content of 2 to 29.5%, a butyryl content of 17 to 53%, and ahydroxyl content of 0.5 to 4.7%; cellulose triacylates having a D.S. of2.9 to 3 such as cellulose trivalerate, cellulose trilaurate, cellulosetripalmitate, cellulose trioctanoate, and cellulose tripropionate;cellulose diesters having a D.S. of 2.2 to 2.6 such as cellulosedisuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulosedicarpylate; cellulose propionate morpholibnobutyrate; cellulose acetatebutyrate, cellulose acetate phthalate, and the like; mixed celluloseesters such as cellulose acetate valerate; cellulose acetate succinate;cellulose propionate succinate; cellulose acetate octanoate; cellulosevalerate palmitate; cellulose acetate heptonate, and the like.Semipermeable polymers are known in U.S. Pat. No. 4,077,407, and theycan be made by procedures described in Encyclopedia of Polymer Scienceand Technology, Vol. 3, pp 325-354, 1964, published by IntersciencePublishers, Inc., New York.

Additional semipermeable polymers that can be used for theirwall-forming properties include cellulose acetaldehyde dimethylcellulose acetate; cellulose acetate ethylcarbamate, cellulose acetatemethylcarbamate; cellulose dimethylaminoacetate, a cellulose compositioncomprising cellulose acetate and hydroxypropyl methylcellulose; acomposition comprising cellulose acetate and cellulose acetate butyrate,a cellulose composition comprising cellulose acetate butyrate andhydroxypropyl methylcellulose; semipermeable polyamides; semipermeablepolyurethanes; semipermeable polysulfanes, semipermeable sulfonatedpolystyrenes, cross-linked, selectively semipermeable polymers formed bythe coprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,641,006, and 3,546,142;selectively semipermeable silicon rubbers; semipermeable polymers asdisclosed by Loeb and Sourirajan in U.S. Pat. No. 3,133,132;semipermeable polystyrene derivatives; semipermeable(polysodiumstyrenesulfonate); semipermeable poly(vinylbenzyltrimethyl)ammonium chloride; semipermeable polymer exhibiting a fluid permeabilityof 10⁻¹ to 10⁻¹⁰ (cc.mil/cm² hr.atm) expressed as per atmosphere orhydrostatic or osmotic pressure difference across a semipermeable wall.The polymers are known to the art in U.S. Pat. Nos. 3,845,770; 3,916,899and 4,160,020, and in Handbook of Common Polymers, by Scott, J. R. andRoff, W. J., 1971, published by CRC Press, Cleveland, Ohio.

The microporous materials used for forming exit means 13 or microporouswall 24 generally can be described as having a sponge-like appearancethat provides a supporting structure for interconnected pores or voids.The material can be isotropic wherein the structure is homogeneousthroughout a cross-sectional area, the material can be anisotropicwherein the structure is nonhomogeneous throughout a cross-sectionalarea, or the materials can have both cross-sectional areas. Themicroporous materials can be opened celled, wherein the pores arecontinuous, or connected pores having an opening on both faces ofmicroporous wall 19. The micropores are interconnected through tortuouspaths of regular and irregular shapes including curved, linear,curvedlinear, randomly oriented continuous pores, hindered connectedpores, and other interconnected porous paths discernible by microscopicexamination.

Generally the microporous materials are characterized as having areduced bulk density as compared to the bulk density of thecorresponding non-porous precursor microporous material. Themorphological structure of the total microporous material will have agreater proportion of total surface area than the non-porous material.The microporous material can be further characterized by the pore size,the number of pores, the tortuosity of the microporous paths, and theporosity which relates to the size and the number of pores. The poresize of a microporous material is easily ascertained by measuring theobserved pore diameter at the surface of the material under the electronmicroscope. Generally materials possessing from 5% to 95% pores, andhaving a pore size of from 10 angstroms to 100 microns can be used formaking wall means 13 and 14. Relationships of the above type arediscussed in Transport Phenomena In Membranes, by Lakshminatayania, N.,Chapter 6, 1969, published by Academic Press, Inc., New York.Microporous materials are described in Science, Vol. 170, pp 1302-1305,1970; Nature, Vol. 214, p 285, 1967, Polymer Engineering and Science,Vol. 11, pp 284-388, 1971; U.S. Pat. Nos. 3,567,809 and 3,751,537; inIndustrial Processing With Membranes, by Lacey, R. E., and Loeb, Sidney,pp 131-134, 1972, published by Wiley Interscience, New York.

Microporous materials are commercially available and they can be made byart known methods The microporous materials can be made by etchednuclear tracking; by cooling a solution of a flowable polymer below thefreezing point whereby the solvent evaporates from the solution in theform of crystals dispersed in the polymer, and then curing the polymerfollowed by removing the solvent crystals; by cold stretching or hotstretching at low or high temperatures until pores are formed; byleaching from a polymer a soluble component by an appropriate solvent;by ion exchange reaction, and by polyelectrolyte processes. In apresently preferred embodiment the microporous means or wall is formedin the environment of use from a precursor microporous means or wallforming material. This latter material contains a pore former that isremoved from the precursor by eroding, dissolving or leaching a poreformer therefrom, thus forming an operable microporous means or wall.The pore formers useful for the present purpose are a member selectedfrom the group consisting of about 1 to 50%, or more, by weight of asolid pore former, about 0.5 to 20%, percent by weight, of a liquid poreformer, and mixtures thereof. In another embodiment the microporousmeans and/or wall can be formed by a compression coating technique. Inthis latter embodiment a rigid microporous material, substantially freeof substances soluble or swellable in the fluid present in theenvironment of use, can be formed by compression coating a microporousmaterial around the compartment forming ingredients. Generally amicroporous means and/or wall is formed under a compression pressure of500 to 5000 kg/cm², usually in a rotary machine. Processes for preparingmicroporous means and walls are described in Synthetic PolymerMembranes, by R. E. Kesting, Chapters 4 & 5, 1971, published byMcGrawHill, Inc.; Chemical Reviews, Ultrafilter Membranes andUltrafiltration, Vol. 18, pp 373-455, 1934; Polymer Engineering andScience, Vol. 11, pp 284-288, 1971; J. Appln. Poly. Sci., Vol. 15, pp811-829, 1971; in U.S. Pat. Nos. 3,565,259, 3,615,024; 3,751,536;3,801,692; 3,852,224; 3,849,528 and 3,929,509; and in Great BritainPatent No. 1,459,356.

Materials suitable for forming a microporous means and/or wall includepolycarbonates comprising linear polyesters of carbonic acid in whichcarbonate groups recur in polymer chains by phosgenation of a dihydroxyaromatic such as a bisphenol; microporous poly(vinyl chloride);microporus polyamides such as polyhexamethylene adipamide; microporousmodacrylic copolymers including those formed of polyvinyl andacrylonitrile; styrene-acrylic acid copolymers; microporous polysulfonescharacterized by diphenylene sulfone groups in the linear chain thereof;halogenated polymers such as polyvinylidene fluoride, polyvinylfluorideand polyfluorohalocarbon; polychloroethers; cellulose esters, celluloseethers, cellulose acylates acetal polymers such a polyformaldehyde,polyesters prepared by esterification of a dicarboxylic acid oranhydride with a polyol; poly(alkylenesulfides); phenols; polyesters;microporous poly(saccharides) having substituted and unsubstitutedanhydroglucose units; asymetric porous polymers; cross linked olefinpolymers; hydrophobic and hydrophilic microporous homopolymers,copolymers or interpolymers having a reduce bulk density, and thematerials described in U.S. Pat. Nos. 3,595,752; 3,643,178; 3,654,066;3,709,774; 3,718,532; 3,803,061, 3,852,224; 3,852,388; 3,853,631; and3,948,254; and in Great Britain patent No. 1,126,849; and in Chem.Absts., Vol. 71, 4274F, 22572F and 22573F, 1969.

Additional microporous materials include materials that aresubstantially insoluble in the fluid present in the environment of use,are inert, non-disintegrating, non-eroding and are materials that can becompressed in powder form, applied by air suspension, dippingtechniques, and the like. Exemplary materials include poly(urethanes);copolymers of divinyl chloride and acrylonitrile; organic materials suchas cross linked, chain extended poly(urethanes); microporouspoly(urethanes) in U.S. Pat. No. 3,524,753; poly(imides);poly(benzimidazoles); collodion(cellulose nitrate with 11% nitrogen);regenerated proteins; microporous materials prepared by diffusion of amultivalent cations into polyelectrolyte sols as in U.S. Pat. No.3,565,259; anisotropic microporous materials of ionically associatedpolyelectrolytes; microporous polymers formed by the coprecipitation ofa polycation and a polyanion as described in U.S. Pat. Nos. 3,276,589;3,541,006; and 3,546,142; derivatives of poly(styrene) such aspoly(sodium styrene sulfone) and poly(vinylbenzyltrimethyl-ammoniumchloride); the microporous materials disclosed in U.S. Pat. Nos.3,615,024; 3,646,178, and 3,852,224; the microporous materials having aplurality of micropores as disclosed in U.S. Pat. No. 3,948,254, and thelike.

The expression, "pore former" includes pore forming solids and poreforming liquids. The later expression, that is, the term, "liquid",generically embraces semi-solids, pastes and viscous fluids. The poreformers can be inorganic or organic. The term, "pore former", for bothsolids and liquids, includes substances that can be dissolved, eroded,extracted or leached from the precursor microporous means or wall byfluid present in the environment of use to form an operable, open celledtype microporous means or wall. Additionally, the pore formers suitablefor the invention include pore formers that can be dissolved, leached,eroded or extracted without causing physical or chemical changes in thepolymer. The pore forming solids can have a size of about 0.1 to 200microns and they include alkali metals salts such as lithium chloride,lithium carbonate, sodium chloride, sodium bromide, sodium carbonate,potassium chloride, potassium sulfate, potassium phosphate, sodiumbenzoate, sodium acetate, sodium citrate, potassium nitrate, and thelike. The alkaline earth metal salts such as calcium phosphate, calciumnitrate, calcium chloride, and the like. The transition metal salts suchas ferric chloride, ferrous sulfate, zinc sulfate, cupric chloride,manganese fluoride, manganese fluorosilicate, and the like. Organiccompounds such as polysaccharides including sucrose, glucose, fructose,mannitol, mannose, galactose, addohexos, altrose, talose, sorbitol, andthe like. Organic aliphatic ols including diols, polyols; organic olsincluding diols and polyols, and other polyols such as polyhydricalcohc1, polyalkylene glycol, polyglycol, poly (α-ω)-alkylenediols, andthe like. The pore formers are non-toxic and on their removal from themeans or wall channels formed through the means or wall that fills withfluid. The channels become, in one embodiment, means or paths forreleasing a beneficial agent from the delivery device. The pores extendfrom the inside means or wall to the outside thereof for effectiverelease of beneficial agent 17 to the exterior of the delivery system10. In a presently preferred embodiment, the means or wall comprises 1to 50% of pore former based on the weight of the polymer of a poreforming agent selected from the group consisting of inorganic salts,organic salts, carbohydrates and ols are used when the pores are formedduring use in a biological environment.

Materials useful for forming internal wall 14 are materials used forforming a capsule. Capsule wall member 14 generally comprises a singlepiece, or a two piece, construction and, in a presently preferredembodiment, it is tubular shaped and it has a mouth at one end, and atthe end distant therefrom it is closed in a hemispherical or dome shapedend. The capsule member serves as a hollow body having a wall thatsurrounds and defines an interior compartment provided with an openingfor establishing communication with the exterior of the capsule and forfilling the capsule. In one embodiment a capsule is made by dipping amandrel, such as a stainless steel mandrel, into a bath containing asolution of a capsule wall forming material to coat the mandrel with thematerial. Then, the mandrel is withdrawn, cooled, and dried in a currentof air. The capsule is stripped from the mandrell and trimmed to yield acapsule with an internal lumen. Materials used for forming capsules arethe commercially available materials including gelatin, gelatin having aviscosity of 15 to 30 millipoises and a bloom strength up to 150 grams;gelatin having a bloom value of 160 to 250; a composition comprisinggelatin, glycerine water and titanium dioxide; a composition comprisinggelatin, erythrosin, iron oxide and titanium dioxide; a compositioncomprising gelatin, glycerine, sorbitol, potassium sorbate and titaniumdioxide; a composition comprising gelatin, acacia, glycerin and water;water soluble polymers that permit the transport of water therethroughand can be made into capsules, and the like.

Expandable means 18 housed in compartment 15 generically comprises, in apresently preferred embodiment, a hydrogel composition. The hydrogelcomposition can be noncross-linked, or it is, optionally, cross-linked,and it possesses properties, such as the ability to absorb and/or imbibean exterior fluid through a semipermeable component of the wall.Hydrogels possessing osmotic properties exhibit an osmotic pressuregradient across said semipermeable wall 12 against a fluid outside ofdelivery system 10. The materials used for forming the expandable,swellable hydrogel means are polymeric materials neat, and polymericmaterials blended with an osmotic agent. These materials in eitherinstant, interact with water or a biological aqueous fluid, absorband/or imbibe fluid and swell or expand to an equilibrium state. Thepolymer exhibits the ability to retain a significant fraction of thefluid in the polymer molecular structure. The polymers presentlypreferred are gels, that is, polymers that can swell or expand to a veryhigh degree, usually exhibiting a 2 to 50 fold volume increase.Hydrophilic polymers that imbibe fluid, swell and expand are known alsoas osmopolymers. The osmopolymers, like other hydrophilic polymers, canbe noncross-linked or lightly cross-linked. The cross-links can becovalent or ionic bonds with the polymer possessing the ability to swellin the presence of fluids. The hydrophilic polymers, when cross-linkedwith nonhydrolyzable bond, will not dissolve in the fluid, but willswell and expand in the presence thereof. The polymers can be of plant,animal or synthetic origin. Polymeric materials useful for the presentpurpose include poly(hydroxyalkyl methacrylate) having a molecularweight of from 5,000 to 5,000,000; poly(vinylpyrrolidone) having amolecular weight of from 10,000 to 360,000; anionic and cationichydrogels; poly(electrolyte) complexes; poly(vinyl alcohol) having a lowacetate residual; a swellable mixture of agar and carboxymethylcellulose; a swellable composition comprising methyl cellulose mixedwith a sparingly cross-linked agar; a water-swellable copolymer producedby a dispersion of finely divided copolymer of maleic anhydride withstyrene, ethylene, propylene, or isobutylene; water swellable polymer ofN-vinyl lactams; and the like.

Other fluid absorbing and/or imbibing and fluid retaining polymersuseful for forming the hydrophilic, expandable push member includepectin having a molecular weight ranging from 30,000 to 300,000;polysaccharides such as agar, acacia, karaya, tragacanth, algins andguar; Carbopol® acidic carboxy polymer and its salt derivatives;polyacrylamides; water-swellable indene maleic anhydride polymers;Good-rite® polyacrylic acid having a molecular weight of 80,000 to200,000; Polyox® polyethylene oxide polymers having a molecular weightof 100,000 to 5,000,000; starch graft copolymers; Aqua-Keep® acrylatepolymers with water absorbability of about 400 times its originalweight; diesters of polyglucan; a mixture of cross-linked polyvinylalcohol and poly(N-vinyl-2-pyrrolidone); zein available as prolamine;poly(ethylene glycol) having a molecular weight of 4,000 to 100,000, andthe like. In a preferred embodiment, the expandable member is formedfrom polymers and polymeric compositions that are thermoformable.Representative polymers possessing hydrophilic properties are known inU.S. Pat. Nos. 3,865,108; 4,002,173; 4,207,893; 4,327,725, and inHandbook of Common Polymers, by Scott and Roff, published by ClevelandRubber Company, Cleveland, Ohio.

The swellable, expandable polymer, in addition to providing a drivingsource for delivering beneficial agent 17 from dispenser 10, furtherserves to function as a supporting matrix for an osmotically effectivesolute. The osmotic solute can be homogeneously or heterogeneouslyblended with the polymer to yield the desirable expandable member 18.The composition in a presently preferred embodiment comprises at leastone polymer and at least one osmotic solute blended together. Generally,a composition will comprise about 20% to 90% by weight of polymer and80% to 10% by weight of osmotic solute, with a presently preferredcomposition comprising 35% to 75% by weight of polymer and 65% to 25% byweight of osmotic solute.

The osmotically effective compound that can be blended homogeneously orheterogeneously with the swellable polymer to form a push or drivingmember are the osmotically effective solutes that are soluble in fluidimbibed across a semipermeable wall and into the swellable polymer. Theosmotically effective compounds exhibit an osmotic pressure gradientacross a semipermeable wall against an external fluid. Osmoticallyeffective compounds are known also as osmotically effective solutes andalso as osmagents. Osmotically effective osmagents useful for thepresent purpose include magnesium sulfate, magnesium chloride, sodiumchloride, lithium chloride, potassium chloride, potassium sulfate,sodium sulfate, mannitol, urea, sorbitol, inositol, succrose, glucose,and the like. The osmotic pressure in atmospheres, ATM, of the osmagentssuitable for the invention will be greater than zero ATM, generally fromeight ATM up to 500 ATM, or higher. Standard procedures for measuringosmotic pressure are known in U.S. Pat. No. 4,331,728 and 4,519,801.

The thermo-responsive composition 16, containing beneficial agent 17homogeneously or heterogeneously dispersed or dissolved therein, isformed in a presently preferred embodiment a heat sensitive, hydrophilicor hydrophobic material that exhibits storage and solid-like propertiesat room temperature of up to 24° C.; and within a few centigrade degreesthereof, and exhibits a dispensing range of 25° C. to 45° C.; and, in apreferred embodiment, a dispensable point that approximates mammalianbody temperatures of 37° C. to 45° C.; and within a few centigradedegrees thereof. The present invention uses the phrases "melting point","melting range", "softening point", "pour point" or "liquifies", toindicate the temperature at which the thermo-responsive compositionmelts, undergoes dissolution, or forms a paste-like ribbon, ordissolves, as it takes up thermal energy or heat, to form a dispensablecarrier 16 so it can be used for dispensing beneficial agent 17 fromdispenser 10.

The term, "thermo-responsive" as used for the purpose of this inventionembraces thermoplastic compositions comprising means for containing abeneficial agent and for forming a dispensable carrier in a biologicalenvironment of use. The thermoplastic composition exhibits means forsoftening or becoming dispensable in response to heat and solidifying orthickening again when cooled. The term also includes thermotropiccompositions capable of undergoing change in response to the applicationof energy in a gradient manner; these are temperature sensitivecompositions in their response to the application or withdrawal ofthermal energy. The term, "thermo-responsive" as used for the purpose ofthis invention in a preferred embodiment denotes the physical-chemicalproperty of a composition agent carrier to exhibit solid, or solid-likeproperties at temperatures up to 24° C.; and become fluid, semisolid orviscous when contacted by heat temperatures from 25° C.; usually in therange of 25° C. to 45° C. The thermo-responsive carrier is heatsensitive and preferably originally anhydrous and it has the property ofmelting, dissolving, undergoing dissolution, softening, or liquefying atthe rising and elevated temperatures, thereby making it possible for thedispenser 10 to deliver the thermo-responsive carrier 16 with thebeneficial agent 17 homogeneously or heterogeneously blended therein.The thermo-responsive carrier generally is lipophilic and hydrophobic,but does not exclude water imiscible and hydrophilic carriers. Anotherimportant property of the carrier 16 is its ability to maintain thestability of agent 17 contained therein during storage and duringdelivery of agent 17. Exemplary of thermoplastic compositions include amember selected from the group consisting of monoglyceride, diglyceride,triglyceride, monoglyceride of a fatty acid, diglyceride of a fattyacid, triglyceride of a fatty acid, glycerides with emulsifier, euteticmixture of mono-, di- and triglycerides, ethoxylated glycerides,partially hydrogenated plant, vegetable and animal fats, hydrogenatedplant, vegetable and animal fats, alklylene glycol fatty and esters,polyalkylene glycol fatty acid esters, triglycerides of fatty acidshaving 12 to 18 carbons, triglycerides of vegetable fatty acids withmonoglycerides, triglycerides of vegetable fatty acid with diglycerides,petroleum-based food grade waxes, and the like. The thermoplasticcomposition is nontoxic and nonirritating to animal tissues, compatiblewith a broad range of active agents, is stable on storage, exhibits abeneficial agent release pattern, and can be used in hand or machinemanufacturing procedures.

Representative thermo-responsive compositions and their melting pointsare as follows: cocoa butter, 32° C.-34° C.; cocoa butter plus 2%beeswax, 35° C.-37° C.; propylene glycol monostearate and distearate,32° C.-35° C.; hydrogenated oils such as hydrogenated vegetable oil, 36°C.-37.5° C.; 80% hydrogenated vegetable oil and 20% sorbitanmonopalmitate, 39° C.-39.5° C.; 80% hydrogenated vegetable oil and 20%polysorbate 60, 36° C.-37° C.; 77.5% hydrogenated vegetable oil, 20%sorbitan trioleate and 2.5% beeswax, 35° C.-36° C.; 72.5% hydrogenatedvegetable oil, 20% sorbitan trioleate, 2.5% beeswax and 5.0% distilledwater, 37° C.-38° C.; mono-, di-, and triglycerides of acids having from8-22 carbon atoms including saturated and unsaturated acids such aspalmitic, stearic, oleic, lineolic, linolenic and archidonic; glyceridesof fatty acids having a melting point of at least 32° C. such asmonoglycerides, diglycerides and triglycerides of vegetable fatty acidshaving 10 to 18 carbon atoms obtained from coconut oil, olive oil andthe like; partially hydrogenated cottonseed oil 35° C.-39° C.; hardenedfatty alcohols and fats, 33° C.-36° C.; hexadienol and anhydrous lanolinthiethanolamine flyceryl monostearate, 38° C.; eutetic mixtures ofmono-, di-, and triglycerides, 35° C.-39° C.; Witepsol® #15,triglyceride of saturated vegetable fatty acid with monoglycerides,33.5° C.-35.5° C.; Witepsol® H32 free of hydroxyl groups, 31`° C.-33°C.; Witepsol® W25 having a saponification value of 225-240 and a meltingpoint of 33.5° C.-35.5° C.; Witepsol® E75 having a saponification valueof 220-230 and a melting point of 37° C.-39° C.; a polyalkylene glycolsuch as polyethylene glycol 1000, a linear polymer of ethylene oxide,38° C.-41° C.; polyethylene glycol 1500, melting at 38° C.-41° C.;polyethylene glycol monostearate, 39° C.-42.5° C.; 33% polyethyleneglycol 1500, 47% polyethylene glycol 6000 and 20% distilled water, 39°C.-41° C.; 30% polyethylene glycol 1500, 40% polyethylene glycol 4000and 30% polyethylene glycol 400, 33° C.-38° C.; mixture of mono-, di-,and triglycerides of saturated fatty acids having 11 to 17 carbon atoms,33° C.-35° C.; block polymer of 1,2-butylene oxide and ethylene oxide;block polymer of propylene oxide and ethylene oxide; block polymer ofpolyoxyalkylene and propylene glycol, food grade wax composition thatsoften continuously in the presence of heat, and the like. Thethermo-responsive composition is a means for storing a beneficial agentas storagable composition at a temperature of up to 24° C. formaintaining an immiscible boundary at the thermo-responsive, swellinginterface, and for dispensing the agent in a flowable composition atemperature greater than 25° C.; and preferably in the range of 25° to45° C. The thermo-responsive composition on being dispensed into abiological environment are easily excreted, metabolized, assimilated, orthe like, for effective use of the beneficial agent.

Representative material for forming the first lamina means 19 formaintaining the separate identity of thermo-responsive composition 16containing agent 17 and expandable member 18 denotes a composition thatpossesses film-forming properties, preferably is soft, flexible andadapts to the configuration of the internal surface of dispenser 10. Ina presently preferred embodiment lamina 19 is a wax. The term as wasused herein generically denotes a petroleum based food-grade wax or anester of a high molecular weight fatty acid with a high molecular weightalcohol. Materials useful for this purpose include waxes, which are adifferent wax composition than a wax comprising the thermo-responsivecomposition; for example, the former can be a higher melting point wax.The waxes acceptable for this present purpose exhibit a melting point ora solidification point of about 45° C. to 110° C. and they are selectedfrom the group consisting of mineral, vegetable, plant, animalpetroleum, and synthetic waxes. Representative waxes include a memberselected from the group including the following wax and its meltingrange: montan wax, 80° C.-90° C.; ozokerite wax, 55° C.- 110° C.;usually 70° C.; carnuba wax, 84° C.-86° C.; myricyl cerotate wax, 85°C.; beeswax, 63° C.; spermaceti, 45° C.; ceresine, 48° C.; gama wax, 47°C.; Japan wax, 63° C.; ouricury, 83° C.; ceresin wax, 68° C.-72° C.;castor wax, 85° C.; Witco wax, 72° C.; and the like. Additionally,reinforcing agents such as cabosil can be incorporated into the wax forimproving structural integrity.

Representative materials for forming lamina 22 for conveying theexpanding force of expandable polymer 18 against thermo-responsivecomposition 16 containing beneficial agent 17 include film-formingpolymer that are capable of receiving and transmitting an applied force,such as olefin polymers, vinyl polymers, synthetic condensationpolymers, natural polymers and organosilicon polymers. Representative ofspecific polymers include polyethylene, polypropylene,polytetrafluoroethylene, polystyrene, polyvinyl acetate, polyvinylformal, cross-linked polyvinyl acetate, polyvinyl butyral, polyacrylate,polymethyacrylate, polyvinyl chloride, cellulose acetate, polyamides,polyester, rubber, styrene butadiene rubber, polyurethane, polysilicone,and the like. The lamina can have a thickness from 1 mil to 15 mm, ormore, for effectively transmitting the in vivo generated force.

The expression, "beneficial agent" as used herein denotes any beneficialagent 17 or compound that can be delivered by device 10 to produce abeneficial and useful result. The beneficial agent can be from insolubleto very soluble in the heat sensitive carrier means 16. The term,"beneficial agent" includes biocide, parasiticide, fungicide, larvicide,flukicide, medicine or drug, nutrient, vitamin, food supplement,mineral, anthelmintic, anti-infestation, growth promotant, ionophores,and other agents that benefit the environment of use.

In the specification and the accompanying claims the term, "beneficialagent" includes any physiologically or pharmacologically activesubstances that produce a local or systemic effect in animals, includingwarm-blooded mammals; humans and primates; household, sport, farm andzoo animals. The term, "physiologically" as used herein denotes theadministration of a drug to produce normal levels and functions. Theterm, "pharmacologically" denotes variations in response to an amount ofdrug administered to the host. Stedman's Medical Dictionary, 1966,published by Williams and Wilkins, Baltimore, Maryland. The beneficiallyactive drugs 17 that can be delivered by device 10 include inorganic andorganic drugs, such as drugs that act on the central nervous system,depressants, hypnotics, sedatives, psychic energizers, tranquilizers,anticonvulsants, muscle relaxants, antiparkinson agents, analgesic,anti-inflamatory, anesthetics, muscle contractants, antimicrobials,antimalarials, hormonal agents, contraceptives, diuretics,sympathomimetics, antiparasitics, neoplastics, hypoglycemics,opthalmics, electrolytes, cardiovascular drugs and the like.

Exemplary drugs that can be delivered by the delivery device areprochlorperazine edisylate, ferrous sulfate, animocaproic acid,potassium chloride, mecamylamine hydrochloride, procainamidehydrochloride, amphetamine sulfate, benzphetamine hydrochloride,isoproterenol sulfate, methamphetamine hydrochloride, phenmetrazinehydrochloride, bethanechol chloride, methacholine chloride, pilocarpinehydrochloride, atropine sulfate, methascopolamine bromide, isopropamideiodide, tridehexethyl chloride, phenformin hydrochloride,methylphenidate hydrochloride, oxprenolol hydrochloride, metroprololtartrate, cimetidine hydrochloride, diphenidol, meclizine hydrochloride,prochlorperazine maleate, phenoxybenzamine, thiethylperazine maleate,anisindone, diphenadione, erythrityl tetranitrate, dizoxin,isofurophate, reserpine, acetazolamide, methazolamide,bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate,phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, erythromycin, progestins, esterogenic steroids,progestational steriods, corticosteroids, hydrocortisone, 17β-estradiol, ethenyl estradiol, ethinyl estradiol 3-methyl ester,prednisolong, hydrocorticosterone acetate, triamcinolone,methyltesterone, 17 β-hydroxyprogesterone acetate, 19-nor-progesterone,norgestrel, norethindone, norethiderone, progesterone, norgesterone,norethynodrel, and the like.

Examples of other beneficial drugs that can be delivered by the deliverydevice include aspirin, indomethacin, naproxen, fenoprofen, sulindac,diclofenac, indoprofen, nitroglycerin, propanolol, valproate, timolol,atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa,chloropromazine, reserpine, methyl-dopa, dihyroxyphenylalanine,prvaloxyloxyethyl ester of α-methyldopa hydrochloride, theophylline,calcium gluconate, ferrous lactate, vincamine, diazepam,phenoxybenzamine, blocking agents, and the like. The beneficial drugsare known to the art in Pharmaceutical Sciences, by Remington, 14th Ed.,1979, published by Mack Publishing Co., Easton, Pennyslvania; The Drug,The Nurse, The Patient, Including Current Drug Handbook, 1974-1976, byFalconer et al, published by Sunder Co., Philadelphia, Pennsylvania, andMedical Chemistry, 3rd Ed., Vol. 1 & 2, by Burger, published byWiley-Interscience, New York.

Representative of beneficial medicaments that can be delivered towarm-blooded animals, exemplified by ruminants, using the deliverysystem of this invention, include anthelmintics such as mebendazole,levamisole, albendazole, cambendazole, fenbendazole, parbendazole,oxfendazole, oxybendazole, thiabendazole, tichlorfon, praziquantel,morantel and parantel, and the like; antiparasitic agents such asavermectin and ivermectin, as disclosed in U.S. Pat. Nos. 4,199,569 and4,389,397, both assigned to Merck & Co., and in Science, Vol. 221, pp823-828, 1983, wherein said ivermectin antiparasitic drugs are disclosedas useful for aiding in controlling commonly occurring infestations inanimals, such as roundworms, lung worms, and the like, and saidivermectin also being useful for the management of insect infestationssuch as grub, lice, mange mite, and the like; antimicrobial agents suchas chlortetracycline, oxytetracycline, tetracycline, streptomycin,gentamicin, dihydrostreptomycin, bacitracins, erthromycin, ampicillins,penicillins, cephalosporins, and the like; sulfa drugs such assulfamethazine, sulfathiazole, and the like; growth stimulants such asMonesin® sodium and Elfazepam®; defleaing agents such as dexamethazoneand flumethazone; rumen fermentation manipulators and ionophores such aslasalocid, virginiamycin, salinomycin and ronnel; minerals and mineralsalts; anti-bloat agents such as organopoly siloxanes; hormone growthsupplements such as stilbestrol; vitamines; antienteritis agents such asfurazolidone; growth efficiency factors such as β-agonists, elenbuterol,nutritional supplements such as lysine monohydrochloride, methionine,magnesium carbonate, ferrous and ferric compounds, copper oxide, cobaltsulphate, sodium selenite, potassium iodide, zinc oxide and managesesulphate, and the like, and chemical markers such as chromic oxide,salts of ytterbium and erbium.

The agents or drugs can be in various forms, such as unchargedmolecules, molecular complexes, pharmacologically acceptable salts suchas hydrochlorides, hydro-bromide, sulfate, laurylate, palmitate,phosphate, nitrate, borate, acetate, maleate, tartrate, oleate,salicylate, and the like. For acid drugs, salts of metals, amines, ororganic cations, for example, quaternary ammonium can be used.Derivatives of drugs such as esters, ethers, amides, and the like, canbe used. Also, an agent or a drug that is lipid insoluble can be usedneat or in a form that is a lipid soluble derivative thereof, and on itsrelease from the device can be converted by body activities tobiologically active forms. Drug that are water insoluble can be in formthat is converted by enzymes, hydrolyzed by body pH or other metabolicprocesses, to the original biologically active form. The amount of drugpresent in a device is initially in a present embodiment, an amount inexcess of the amount that can be dissolved in the heat sensitiveformulation. Generally, the device can contain from 0.05 ng to 5 g ormore, with individual devices containing, for example, 25 ng, 1 mg, 5mg, 125 mg, 500 mg, 750 mg, 1.5 g, 10 g, 25 g, 1023 50 g, and the like.The device can dispense from 0.1 to 1500 mg/hr. For example, foravermectins such as ivermectin the device can be dispensed over adispensing range of 1 mg/day to 50 mg/day and the like. The devices candispense agent from 1 day to 6 months or more.

The term, "animal" as used herein generically denotes an animal and itsnormal average temperature in centigrade, usually measured rectally, asfollows: man, 37° C.; camel, 37° C.-38° C.; cattle, 38° C.-39° C.; dog,38° C. -39° C.; goat, 38° C.-39° C.; sheep, 39° C.-40° C.; swine, 37°C.-38° C.; deer, 38° C. 39° C.; bison, 39° C.; giraffe, 3720 C.-38° C.;horse, 38° C.; and elephant, 36° 37° C.

The expression, "means for releasing a beneficial agent" as used hereinincludes at least one preformed passageway, or at least one passagewayformed when the device is in use. The passageway in either embodimentwill pass through the wall for communicating with the compartment forreleasing the beneficial agent from the device. The expression, "meansfor releasing beneficial agent" includes passageway, aperture, bore,pore, porous element through which the beneficial agent can migrate,hollow fiber, capillary tube, microporous member, and the like. Themeans for releasing agent include a material that is removed from thewall during use such as eroding in the environment of use to produce atleast one passageway in the device. Representative materials suitablefor forming a passageway include erodible poly(glycolic), poly(lactic)in the wall, gelatinous filaments, poly(vinyl alcohol), and the like.The passageway can be formed by leaching a material such as sorbitolfrom the wall. The passageway can have any shape such as round,triangular, square, elliptical, irregular, and the like. The device canbe constructed with more than one passageway, especially for dispensingreleased agent over a wide area. In a preferred embodiment, when thedevice is fabricated with more than one passageway, they can beconstructed as the functional equivalent of a single passageway. Thepassageway can be formed also by mechanical drilling or laser drillingthrough the wall. A description of means for releasing a beneficialagent as described herein is disclosed in U.S. Pat. Nos. 3,845,770 and3,906,899. Procedures for forming at least one passageway of governedporosity by leaching from a wall, such as a cellulose wall, a poreformer is disclosed in U.S. Pat. Nos. 4,200,098; 4,235,236; 4,309,996,and 4,320,759. The leaching or dissolving of a pore former from a wallforming material is known also in U.S. Pat. Nos. 4,256,108; 4,265,874and 4,344,929. Laser drilling equipment having photo detection means fororienting a device for selecting a surface for drilling a passageway forcommunicating with a preselected area inside a device is known in U.S.Pat. Nos. 4,063,064 and 4,008,864.

The wall, including the semipermeable wall, the microporous wall and thelaminated wall can be formed by molding, air spraying, dipping orbrushing with a wall forming composition. Other and presently preferredtechniques that can be used for applying wall forming materials are theair suspension procedure and the pan coating procedure. The airprocedure consists in suspending and tumbling the compartment formingmaterials in a current of air and a wall forming composition until thewall surrounds and coats the materials. The procedure can be repeatedwith a different wall forming composition to form a laminated wall. Theair suspension procedure is described in U.S. Pat. No. 2,799,241; J. Am.Pharm. Assoc., Vol. 48, pp 451 to 459; and ibid, Vol. 49, pp 82 to 84,1960. Other standard manufacturing procedures are described in ModernPlastics Encyclopedia, Vol. 46, pages 62 to 70, 1969; and inPharmaceutical Sciences, by Remington, 14th Ed., pp 1626 to 1678, 1970,published by Mack Publishing Co., Easton, PA.

Exemplary solvents suitable for manufacturing the walls include inertinorganic and organic solvents that do not adversely harm the materials,the wall, the beneficial agent, the thermo-responsive composition, theexpandable member, and the final dispenser. The solvents broadly includemembers selected from the group consisting of aqueous solvents,alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenatedsolvents, cycloaliphatics, aromatics, heterocyclic solvents and mixturesthereof. Typical solvents include acetone, diacetone alcohol, methanol,ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethylacetate, isopropyl alcohol, n-gutyl acetate, methyl isobutyl ketone,methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethylether, ethylene glycol monoethyl acetate, methylene dichloride, ethylenedichloride, propylene dichloride, carbon tetrachloride, nitroethane,nitropropane, tetrachloroethane, ethyl ether, isopropyl ether,cyclohexane, cyclo-octane, benzene, toluene, naptha, 1,4-dioxane,tetrahydrofuran, diglyme, water, and mixtures thereof such as acetoneand water, acetone and methanol, acetone and ethyl alcohol, methylenedichloride and methanol, and ethylene dichloride and methanol.Generally, for the present purpose the wall is applied at a temperaturea few degrees less than the melting point of the thermo-responsivecomposition. Or, the thermoplastic composition can be loaded into thedispenser after applying the wall.

DESCRIPTION OF EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be construed as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomemore apparent to those skilled in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

EXAMPLE 1

A dispensing system manufactured in the shape of a dispenser for thecontrolled delivery of ivermectin is made as follows: First, 193 g ofButronic® L-1 polyol, a block polymer formed by the polymerization of1,2-butylene oxide to which ethylene oxide, is added, as reported inCosmetics and Toiletries, Vol. 97, pp 61-66, 1982, which polymer flow ata pour point of 39° C.; is melted at 55° C.; and then 13.98 g ofivermectin is added thereto using a high sheer ultrasonic mixer. Theresulting mixture is placed in a vacuum oven at 55° C. and the pressurereduced to less than 10 mm of mercury. The ivermectin Butronic®composition is allowed to remain in the vacuum for a period of about 10minutes, for removing entrapped air. Next, 4 g of the resultingthermoplastic drug formulation is poured into a gelatin capsule that ispreviously charged with a 33 g stainless steel density member having abore therethrough. Then, 2 g of beeswax, melted at 63° C.; is chargedonto the thermoplastic composition to form a contacting lamina. The waxis substantially impermeable to the passage of water for substantiallyrestricting any extraction of the active agent by an aqueous type fluidthat is absorbed into the dispenser by the expandable polymer. Then, anexpandable driving member comprising 2.1 g of sodium chloride and 4.9 gof the sodium salt of polyacrylic acid available as Carbopol® 934P iscompressed into a tablet. The tablet is formed using a 18.2 mm tabletingtool and 3 1/2 tons of compression force. The tablet has a final shapethat corresponds to the internal shape of the opening of the capsule.The tablet member then is inserted into the opened end of the capsuleuntil contact is made with the drug polyol formation. Next, the capsuleis coated in a pan coater with a rate controlling wall comprising 1.8 gof 91% cellulose acetate butyrate and 9% polyethylene glycol 400. Thewall is coated from a 5% wt/wt solution in methylene chloride methanol90:10 v/v solvent system. The wall coated delivery systems then aredried at 30° C. for 24 hours. Next, a 30 mil exit passageway is drilledthrough the semipermeable wall using a high speed mechanical drill forcommunicating the passageway with the bore. The passageway borearrangement established communication with the heat-responsive drugformulation for delivering it from the delivery system. The dispensermade according to this example has an average release rate of 0.6 mg perhour over a 480 hr period of time.

EXAMPLE 2

A delivery system is made according to the procedure set forth inExample 1, with the conditions as set forth, except that in this examplethe heat-responsive composition comprises 46.6 g of ivermectin and 200 gof polyethylene glycol 400 distearate, the intermediate lamina comprisesouricury wax that is added in a lamina forming amount at a temperatureof about 82° C. to 84° C.; and the expandable-swellable compositioncomprises 70% by weight of poly(ethylene oxide) having a molecularweight of 3,000,000 and 30% by weight of sodium chloride.

EXAMPLE 3

A dispensing system is prepared for manufacturing a dispenser accordingto the procedure of Example 1, with the conditions as previously setforth, except that in this example the thermo-responsive compositioncomprises a food grade Witco multiwax that is soft at a temperature of35° C. and softens in the presence of rising temperatures from 35° C. to40° C. and can be dispensed from the dispensing system under ahydrostatic pressure of 8 to 12 psi.

EXAMPLE 4

A dispenser is prepared as follows: First, the body section of a capsuleis positioned with its mouth in an upright position, and a densestainless steel element inserted into the hemispherical end of thecapsule. The density element is machined and its shape matches theinternal shape of the capsule. Next, a layer of an expandable-swellablecomposition is charged on top of the density element. The compositioncomprises 25% by weight of sodium chloride and 75% by weight ofpoly(ethylene oxide) having a molecular weight of 200,000. Theexpandable forming ingredients are blended in a commercial blender withheat for 20 minutes to yield a homogeneous composition. The heatcomposition is charged into the capsule forming a layer that occupiesabout 1/3 of the capsule. Next, a lamina comprising polyethylene andstamped-cut to have a shape that corresponds to the internal shape ofthe capsule is placed against the expandable layer in contactingarrangement. Then, a lamina comprising 2 g of melted beeswax is chargedinto the capsule in laminar arrangement with the previously positionedlamina, and the manufacture allowed to cool to room temperature, about22° C. Next, a heat-sensitive drug formulation comprising an euteticmixture of 77% neutral fat having a melting point of 35° C.-37° C. and19.5% paraffin having a melting point of 52° C. is heated and 3.5%levamisole is added thereto. Then, the heated mixture is cooled to about40° C. and injected into the capsule in contacting relation with theexpandable layer, and the capsule allowed to cool to room temperature.

Then, a solution of cellulose acetate, 15 wt percent, with an acetylcontent of 39.8%, is prepared in a methylene chloride-methanol solventsystem and the capsule coated with a semipermeable wall. The wall isapplied by dipping it into the coating solution 15 times, first for a 5second dip, then for two 10 second dips, then for a 30 second dip andthen for 1 minute per dip, with an intervening 5 minute drying period.Following the dipping the delivery dispenser is dried at roomtemperature, 72° F., about 22° C.; for 5 days. The procedure appliesabout a 2 mm thick semipermeable wall. A passageway is laser drilledthrough the semipermeable wall connecting the exterior of the dispenserwith the heat sensitive drug formulation for releasing it at acontrolled rate over time.

EXAMPLE 5

A dispensing system for delivering beneficial nutrients to warm-bloodedruminants is prepared as follows: First, a mold having a shape andconfiguration corresponding to the internal diameter and thehemispherical closed end of a wide-mouth capsule is filled with anexpandable forming composition comprising 30 parts of ethyleneglycolmonomethacrylate containing 0.12 parts of ethyleneglycol dimethacrylateand 10 parts of a 0.13% aqueous solution of sodium disulfate in aqueousethanol. The composition polymerizes at 30° C.; and after 20 minutesfollowing equilibrium to room temperature, the solid layer is removedfrom the mold. The solid expandable layer then is inserted through themouth of the capsule into the hemispherical area of the capsule. Then, alamina of paraffin wax having a melting point of about 52° C. is addedto the subassembly and, after cooling, a dense member made of stainlesssteel machined in the shape of a tablet is placed inside the capsule incontacting laminar arrangement with the expandable layer. Next, theremainder of the capsule is filled with a melted composition comprising2.5% L-lysine HCl, 1.5% DL-methionine, 21% glycergelatin and 75%theobromo oil, a glyceride of stearic acid, palmitic acid and lauricacid, to form, on cooling to room temperature, the thermo-responsivecomposition in laminar position with the dense member. Next, the filledcapsule is coated with a surrounding wall comprising cellulose acetatecontaining 10% polyethylene glycol 400. The semipermeable wall isapplied in a pan type Hi-coater. The solvent used for forming the wallconsists essentially of methylene chloride and methanol 95 parts byweight to 5 parts by weight. A 12 mil, 0.30 mm, thick wall of celluloseacetate butyrate is applied to the exterior surface of the capsule.Finally, an exit means in the form of a passageway is laser drilledthrough the semipermeable wall communicating with the heat-responsivenutrient containing composition for its delivery to the environment ofuse.

EXAMPLE 6

A delivery system is made according to the procedure set forth inExample 1, with the conditions and materials as set forth, except thatin this example a varying rate controlling wall thickness comprising acomposition of cellulose acetate butyrate and polyethylene glycol 400 isapplied to the system. The thickness of the rate controlling wall variesfrom 30 mil, 0.76 mm, at the end distant from the passageway in auniform taper to 15 mil, 0.38 mm, adjacent to the density member.Accompanying FIG. 18 depicts the amount of ivermectin antiparasiticreleased from the system over a prolonged period of 480 hours, and FIG.19 depicts the cumulative amount of ivermectin released over the 480hour period. The bars represent the minimum and maximum variation forthe release rate at the time of measurement.

EXAMPLE 7

A delivery system is made according to the procedure as set forth inExample 1, with all conditions and materials as previously described,except for the semipermeable wall that comprises 50% cellulose acetatebutyrate, 45% poly(sulfone) and 5% citroflex citric acid ester selectedfrom the group consisting of acetyl tributyl citrate and acetyltri-2-ethylhexyl citrate.

EXAMPLE 8

A delivery system is made according to the procedure as set forth inExample 1, with all conditions as described except that the wall in atleast a part comprises 80% cellulose acetate butyrate and 20%poly(sulfone), or the wall comprises 20% cellulose acetate butyrate and80% poly(sulfone).

EXAMPLE 9

A delivery device manufactured in the shape of an oral dispenser for thecontrolled delivery of indomethacin is made as follows: First, 300 mg ofButronic® L-1 polyol, a block polymer formed by the polymerization of1,2-butylene oxide to which ethylene oxide is added, as reported inCosmetics and Toiletries, Vol. 97, pages 61-66, 1982, which polymer flowat a pour point of 39° C.; is melted at 55° C. and then 200 mg ofindomethacin is added thereto using a high sheer ultrasonic mixer. Theresulting mixture is placed in a vacuum oven at 55° C. and the pressurereduced to less than 10 mm of mercury. The indomethacin Butronic®composition is allowed to remain in the vacuum for a period of about 10minutes, for removing entrapped air. Next, 400 mg of the resultingheat-sensitive thermoplastic drug formulation is poured into an openedmouth gelatin capsule. Then, an intermediate lamina forming composition.pa comprising melted paraffin is placed immediately against theheat-sensitive drug formulation. Next, an expandable driving membercomprising 100 mg of sodium chloride and 200 mg of the sodium salt ofpolyacrylic acid available as Carbopol® 934P as compressed into atablet. The tablet is formed using a 10 mm tableting tool and 3 1/2 tonsof compression force. The tablet has a final shape that corresponds tothe internal shape of the opening of the capsule. The tablet member thenis inserted into the opened end of the capsule until contact is madewith the drug polyol formation. Next, the capsule is coated in a pancoater with a rate controlling wall comprising 1.8 g of 91% celluloseacetate butyrate and 9% polyethylene glycol 400. The wall is coated froma 5% wt/wt solution in methylene chloride methanol 90:10 v/v solventsystem. The wall coated delivery systems then are dried at 30° C. for 24hours. Next, an exit means shaped in the form of a 30 mil exitpassageway is drilled through the semipermeable wall using a high speedmechanical drill for communicating with the heat-responsive drugformulation for delivering it from the delivery device.

EXAMPLE 10

A delivery system is made according to the procedure set forth inExample 8, with the conditions as set forth, except that in this examplethe heat-responsive composition comprises polyethylene glycol 400distearate, and the expandable-swellable composition comprises 70% byweight of poly(ethylene oxide) having a molecular weight of 3,000,000and 30% by weight of sodium chloride.

EXAMPLE 11

A dispenser system is prepared as follows: First, the body section of acapsule is positioned with its mouth in an upright position, and then alayer of an expandable-swellable composition is charged into thehemispherical end of the capsule. The composition comprises 25% byweight of the osmotic solute sodium chloride and 75% by weight of theosmopolymer poly(ethylene oxide) having a molecular weight of 200,000.The expandable forming ingredients are blended in a commercial blenderwith heat at 30° C. for 20 minutes to yield a homogeneous composition.The heated composition is charged into the capsule forming a layer thatoccupies about 1/3 of the capsule. Next, a layer of candelilla wax,having a melting point of about 67° C.; is placed against the cooledexpandable composition. Then, a heat-sensitive drug formulationcomprising an eutectic mixture of 77% neutral fat, having a meltingpoint of 35° C.-37° C.; and 19.5% paraffin, having a melting point of52° C.; is heated and 3.5% 2-acetoxybenzoic acid is added thereto. Then,the heated mixture is cooled to about 40° C. and injected into thecapsule in contacting relation with the expandable layer, and thecapsule allowed to cool to room temperature.

Then, a solution of cellulose acetate, 15 wt %, with an acetyl contentof 39.8%, is prepared in a methylene chloride methanol solvent systemand the capsule coated with a semipermeable wall. The wall is applied bydipping it into the coating solution 15 times, first for a 5 second dip,then for two 10 second dips, then for a 30 second dip and then for 1minute per dip, with an intervening 5 minute drying period. Followingthe dipping the delivery dispenser is dried at room temperature, 72° C.;about 22° C.; for 5 days. The procedure applies about a 2 mm thicksemipermeable wall. A passageway is laser drilled through thesemipermeable wall connecting the exterior of the dispenser with theheat sensitive drug formulation for releasing it at a controlled rateover time.

EXAMPLE 12

A dispensing device for delivering a beneficial agent to a warm-bloodedanimal is prepared as follows: First, a mold is filled with anexpandable forming composition comprising 30 parts of ethyleneglycolmonomethacrylate containing 0.12 parts of ethyleneglycol dimethacrylateand 10 parts of a 0.13% aqueous solution of sodium disulfate in aqueousethanol. The composition polymerizes at 30° C.; and after 20 minutesfollowing equilibrium to room temperature, the solid layer is removedfrom the mold. Next, a layer of paraffin having the same shape and sizeas the expandable composition is placed in laminating arrangement withthe expandable composition. Then, a layer of a heat-sensitive carriercomprising cocoa butter plus 2% beeswax and 250 mg of oxprenololhydrochloride is placed in contacting arrangement with the expandablecomposition. Then, the laminated arrangement is coated by quick dippingwith a wall forming microporous composition consisting essentially of45% by weight of cellulose acetate having an acetyl content of 39.8%,45% by weight of sorbitol and 10% by weight of polyethylene glycol 400.Then, a semipermeable wall is coated onto a part of the microporouswall, except for an uncoated drug releasing surface. The semipermeablewall comprises 50% by weight of cellulose acetate having an acetylcontent of 39.8% and 50% by weight of cellulose acetate having an acetylcontent of 32%.

EXAMPLE 13

A delivery system is made according to the procedure set forth Example1, with the conditions and materials as set forth, except that in thisexample the device comprises a single wall of a varying thickness ofcellulose acetate butyrate and polyethylene glycol 400. The thickness ofthe rate controlling wall varied from 30 mil, 0.76 mm, at the end ofdevice 10 to a uniform taper of 15 mil, 0.38 mm, next to the passageway.

An embodiment of the invention pertains to a method of increasing thedeliverability of a beneficial agent by formulating a heat-sensitivecomposition containing a beneficial agent and making the delivery systemof the invention for increasing the deliverability of the beneficialagent. An embodiment of the invention pertains also to a method foradministering a beneficial drug at a controlled rate orally to ananimal, which method comprises the steps of: (A) admitting into theanimal a dispensing device comprising: (1) an outer wall comprising in aleast a part a semipermeable polymeric composition permeable to thepassage of fluid and substantially impermeable to the passage of drug,the wall surrounding (2) an internal lumen containing a layer of abeneficial drug formulation comprising a dosage unit for preforming atherapeutic program in a heat-sensitive pharmaceutically acceptablecarrier that melts at body temperature and is a means for transportingthe drug from the dispenser; (3) a layer of a means for increasing thedeliverability of beneficial agent from the device; (4) a layer of anexpandable hydrogel in the lumen; (5) an optional layer of a densemember for maintaining the dispenser in the rumen over a prolongedperiod of time when the dispenser is administered to a ruminant, and (6)releasing means in the wall communicating with the heat-sensitive drugformulation; (B) imbibing fluid through the semipermeable part of thewall at a rate determined by the permeability of the semipermeable walland the osmotic pressure gradient across the semipermeable wall and theosmotic pressure gradient across the semipermeable wall causing thelayer of expandable hydrogel to expand and swell; (C) melting the drugformulation to form a flowable formulation, and (D) delivering thebeneficial drug formulation from the compartment by the expandable layercontinually expanding against the intermittent layer and consequentlyagainst the melting formulation causing the formulation to be dispensedin a therapeutically effective amount through the exit means at a ratethe expansion of the hydrogel, the melting of the formulation and theosmotic properties of the dispenser over a prolonged period of time.

Inasmuch as the foregoing specification comprises preferred embodimentsof the invention, it is understood that variations and modifications maybe made herein in accordance with the inventive principles disclosed,without departing from the scope of the invention.

We claim:
 1. A dispensing device for delivering a beneficial agentformulation to an environment of use, the dispensing devicecomprising:(a) wall means that surrounds and defines an internalcompartment, said wall means comprising at least in part a compositionpermeable to the passage of fluid present in the environment of use; (b)thermoplastic means in the compartment for absorbing thermal energy fromthe environment of use for dispensing a beneficial agent; (c) abeneficial agent present in the thermoplastic means for absorbingthermal energy for dispensing the beneficial agent; (d) a hydrophilicosmopolymer in the compartment for expanding, occupying an increasingarea of the compartment, and for pushing the thermoplastic means fromthe compartment; (e) lamina means for enhancing the amount of beneficialagent delivered from the dispensing device in the compartment positionedbetween the thermoplastic means and the hydrophilic osmopolymer; and (f)exit means in the wall for releasing the beneficial agent from thedispensing device to the environment of use over time.
 2. The dispensingdevice for delivery the beneficial agent formulation to the environmentof use according to claim 1, wherein the hydrophilic osmopolymercomprises an osmagent.
 3. The dispensing device for delivering thebeneficial agent formulation to the environment of use according toclaim 1, wherein the wall means comprises in at least a part asemipermeable composition.
 4. The dispensing device for delivering thebeneficial agent formulation to the environment of use according toclaim 1, wherein the exit means in the wall for delivering thebeneficial agent comprises at least one passageway.
 5. The dispensingdevice for delivering the beneficial agent formulation to theenvironment of use according to claim 1, wherein the exit means in thewall for delivering the beneficial agent comprises at least onepassageway formed in the environment of use.
 6. The dispensing devicefor delivering the beneficial agent formulation to the environment ofuse according to claim 1, wherein the wall means that surrounds anddefines the compartment comprises in at least a part a microporouspolymer member.
 7. The dispensing device for delivering the beneficialagent formulation to the environment of use according to claim 1,wherein the wall means that surrounds and defines the compartmentcomprises in at least a part an impermeable polymer member.
 8. Thedispensing device for delivering the beneficial agent formulation to theenvironment of use according to claim 1, wherein the exit means in thewall for delivering the beneficial agent from the device comprises apassageway forming material that is removed therefrom by fluid presentin the environment of use.
 9. The dispensing device for delivering thebeneficial agent formulation to the environment of use according toclaim 1, wherein the wall means comprises a microporus member laminatedin part to a semipermeable member.
 10. The dispensing device fordelivering the beneficial agent formulation to the environment of useaccording to claim 1, wherein the thermoplastic means form a dispensablecomposition at a temperature greater than 25° C.
 11. The dispensingdevice for delivering the beneficial agent formulation to theenvironment of use according to claim 1, wherein the wall meanscomprises a member selected from the group consisting of a celluloseester, cellulose diester, cellulose triester, cellulose ether, celluloseester-ether, cellulose acylate, cellulose diacylate, cellusosetriacylate, cellulose acetate, cellulose acetate butyrate, cellulosepropionate morphilinobutyrate, and cellulose aetate phthalate.
 12. Thedispensing device for delivering the beneficial agent formulation to theenvironment of use according to claim 1, wherein the wall meanscomprises a member selected from the group consisting of a celluloseester, cellulose diester, cellulose triester, cellulose ether, celluloseester-ether, cellulose acylate, cellulose diacylate, cellusosetriacylate, cellulose acetate, cellulose acetate butyrate, cellulosepropionate morphilinobutyrate, and cellulose aetate phthalate, and apore former.
 13. A dispensing device for delivering a beneficial agentformulation to an environment of use, the dispensing systemcomprising:(a) a hollow body member having an internal lumen; (b) athermoplastic heat-sensitive beneficial agent formulation in the lumenthat forms a deliverable formulation at a temperature of at least 25°C.; (c) hydrogel means in the lumen for expanding from a first size toan increased size; (f) laminar means in the lumen for lessening themixing of the thermoplastic means with hydrogel means, said laminarmeans positioned between the thermoplastic means and the hydrogel means;(e) a wall surrounding the hollow body, the wall comprising in at leasta part a composition that is permeable to the passage of fluid; and, (f)at least one passageway means in the wall communicating with the lumenfor delivering the formulation to the environment of use at a controlledrate over a prolonged period of
 14. A dispensing device for delivering abeneficial agent formulation to an environment of use, the deliveringsystem comprising:(a) a wall that surrounds and defines an internallumen, the wall comprising in at least in part a semipermeablecomposition that is permeable to the passage of fluid and substantiallyimpermeable to the passage of a beneficial agent; (b) means in the lumenfor maintaining the delivery system in the environment of use over time,said means having a density of at least 1.2; (c) hydrogel means in thelumen for expanding and occupying an increased volume of the lumen; (d)a heat-sensitive means in the lumen that forms a dispensable carrier ata temperature greater than 25° C.; (e) a beneficial agent present in theheat-sensitive means; (f) lamina means in the lumen between the hydrogelmeans and the heat-sensitive means, said lamina means positioned therebetween for lessening the migration of beneficial agent from theheat-sensitive means into the hydrogen means; and, (g) exit means in thewall for communicating with the lumen for delivering the beneficialagent to the environment of use over time.
 15. The delivery system fordelivering a beneficial agent formulation according to claim 14, whereinthe beneficial agent formulation is avermectin.
 16. The delivery systemfor delivering a beneficial agent formulation according to claim 14,wherein the beneficial agent formulation comprises ivermectin.
 17. Thedelivery system for delivering a beneficial agent formulation accordingto claim 14, wherein the heat-sensitive beneficial agent formulationcomprises a block copolymer comprising 1,2-butylene oxide and ethyleneoxide and ivermectin.
 18. The delivery system for delivering abeneficial agent formulation according to claim 14, wherein theheat-sensitive means comprises a food grade wax and ivermectin.
 19. Thedelivery system for delivering a beneficial agent formulation accordingto claim 14, wherein the hydrogel means comprises a sodium salt ofpolyacrylic acid and sodium chloride.
 20. The delivery system fordelivering a beneficial agent formulation according to claim 14, whereinthe wall comprises cellulose acetate butyrate and polyethylene glycol.21. The delivery system for delivering a beneficial agent formulationaccording to claim 14, wherein the means for maintaining the deliverysystem in the environment of use comprises a member selected from thegroup consisting of iron, steel, iron magnesium alloy, and a mixture ofcobalt and iron.